Lung cancer is the leading cause of cancer death in the United States and world-wide, with over 85% of cases due to non-small cell lung cancer (NSCLC). The goal of our Program is to advance the pre-clinical science of NSCLC therapeutics. During the current funding period, our Program has advanced inhibitors of EGFR, promoting the pre-clinical development of osimertinib and related molecules, of TBK1, and of DDR2. In its next 5 years, our Program aims to develop compounds that will lead to more effective treatments for NSCLC and prevent or overcome resistance to existing and future targeted therapies. To accomplish these goals, the Program seeks to achieve the following overall aims via 3 inter-related and collaborative Projects and 4 intellectually driven Shared Resource Cores. --Overall Aim 1. Develop inhibitors and/or degraders focused on mutant EGFR, KRAS signaling effectors, and mechanisms of transcriptional adaptation in non-small cell lung cancer. --Overall Aim 2. Characterize these compounds and their targets pharmacologically using genetically defined cellular and animal models of lung cancer. --Overall Aim 3. Develop and assess combinations of these potent and selective novel agents with existing therapies to prevent and overcome therapeutic resistance. These aims leverage innovations in chemistry and structural biology?the development of allosteric kinase inhibitors and selective degraders?coupled with expertise in lung cancer biology, lung cancer cellular and animal modeling, and functional genomic approaches to understanding pathways, through the Projects and Cores. The broad aims will be implemented with three focused projects aimed at developing inhibitors of key pathways in NSCLC as well as over-arching mechanisms of resistance: --Project 1: Development of pharmacologic strategies to degrade mutant EGFR. --Project 2: Identification of combination therapy for KRAS-driven lung cancers. --Project 3: Targeting transcriptional mechanisms of therapeutic resistance in non-small cell lung cancer. Each Project and the overall Program is based on the innovative, technology-driven Cores, each led by faculty with expertise in the specific areas. Core A: Medicinal Chemistry. Core B: Structure and Biochemistry. Core C: Animal Modeling and Preclinical Therapeutics. Core D: Program Administration. The integration of the three Projects and the four Cores will enable an effective co-ordination to meet Program aims by cross-fertilization of lung cancer focus and technological expertise.